1108743-60-7

Basic information

• Product Name: Entrectinib
• Synonyms: Entrectinib;Entrectinib(NMS-E628);N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide;RXDX-101;Entrectinib,NMS-E628,RXDX-101;entrecitinib;Entrectinib(RXDX-101);NMS-E628
• CAS NO: 1108743-60-7
• Molecular Formula: C₃₁H₃₄F₂N₆O₂
• Molecular Weight: 560.6374664
• Product Categories: API;API
• Mol File: 1108743-60-7.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 717.5±60.0 °C(Predicted)
• Appearance: /
• Density: 1.340±0.06 g/cm3(Predicted)
• Solubility: ≥28.05 mg/mL in DMSO; insoluble in H2O; ≥9.82 mg/mL in EtOH with ultrasonic
• PKA: 12.01±0.43(Predicted)
• CAS DataBase Reference: Entrectinib(CAS DataBase Reference)
• NIST Chemistry Reference: Entrectinib(1108743-60-7)
• EPA Substance Registry System: Entrectinib(1108743-60-7)

Safety Data

• Hazardous Substances Data: 1108743-60-7(Hazardous Substances Data)

Usage

Description

Entrectinib, also known as RXDX-101 and NMS-E628, is an oral small molecule inhibitor of TrkA, TrkB, TrkC, ROS1, and ALK, with high potency and selectivity. It has demonstrated potent pharmacological activity in preclinical studies and has the potential to be first-in-class against the Trk family of kinases. Entrectinib is used to treat metastatic non-small cell lung cancer (NSCLC) caused by the ROS1 gene and solid tumors caused by certain abnormal NTRK genes. It is designed to cross the blood-brain barrier and has been well tolerated in patients with advanced solid tumors. Entrectinib is currently in clinical trials and is being developed by Ignyta.

Uses

Used in Oncology:
Entrectinib is used as an antineoplastic agent for the treatment of metastatic non-small cell lung cancer (NSCLC) caused by the ROS1 gene. It inhibits the tyrosine kinases TRKA/B/C, ROS1, and ALK, blocking proliferation of ALK-dependent cell lines and inhibiting ALK-dependent signaling, leading to tumor regression in mice bearing various Trk, ROS1, or ALK-driven xenografts.
Used in Solid Tumor Treatment:
Entrectinib is used as a targeted therapy for the treatment of solid tumors caused by certain abnormal NTRK genes. It is particularly useful in cases where surgery to remove the cancer is likely to cause severe complications, and there is no acceptable treatment option or the cancer has grown or spread on other treatments.
Used in the Treatment of Cancers with Resistance Mutations:
Entrectinib is used as an inhibitor for blocking the proliferation of ALK-dependent cell lines, including those with L1196M or C1156Y resistance mutations. It has been shown to inhibit the growth of a non-small cell lung cancer cell line bearing an EML4-ALK rearrangement, making it a potential treatment option for patients with resistance mutations.
Used in the Treatment of Cancers with Central Nervous System Involvement:
Entrectinib is used as a treatment option for cancers that have spread to the central nervous system, as it was specifically designed to cross the blood-brain barrier. This property makes it a valuable agent for targeting cancer cells in the brain and potentially improving patient outcomes.

Effect and benefit

Entrectinib belongs to the group of medicines called antineoplastics (cancer medicines). It works by interfering with the growth of cancer cells, which are eventually destroyed.

Mechanism of action

An inhibitor of tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK); also, inhibits JAK2 and TNK2. Major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation.

Safety

Entrectinib exhibits hepatic metabolism through cytochrome P450 (CYP) 3A and therefore interacts with moderate-strong CYP3A inhibitors and inducers. In addition, due to its effects on the QTcF interval, use of entrectinib should be avoided with other drugs known to prolong the QT/QTc interval.

Pharmacology

Entrectinib, is a weak P-gp substrate that can sustain CNS exposure based on our novel in vitro and in vivo experiments. This is consistent with the observed preclinical and clinical efficacy of entrectinib in neurotrophic tropomyosin receptor kinase (NTRK) and ROS1 fusion-positive CNS tumors and secondary CNS metastases.

Clinical Use

Entrectinib demonstrated potent antitumor effects in tumor cell lines and patient-derived xenograft (PDX) tumor models in preclinical studies. Furthermore, entrectinib can cross the blood–brain barrier (BBB) to impact primary brain tumors and brain metastases in patients with NTRK1/ NTRK2/NTRK3, ROS1, and ALK fusion-driven cancers.

in vitro

entrectinib potently and selectively inhibits the in vitro growth of alk-driven tumors, with confirmed mechanism of action [1].

in vivo

since entrectinib is able to pass the blood-brain barrier, the compound was also tested for efficacy in an xenograft model with alk positive nsclc tumors. mri imaging demonstrated that entrectinib was able to effectively and control the growth of these intracranial tumors dose-dependently, leading to increased survival [1].

references

[1] elena ardini, maria menichincheri, patrizia banfi, daniele casero, m. laura giorgini, m. beatrice saccardo, nadia amboldi, nilla avanzi, paolo orsini, antonella isacchi, enrico pesenti, arturo galvani. the alk inhibitor nms-e628 also potently inhibits ros1 and induces tumor regression in ros-driven models. [abstract]. in: proceedings of the 104th annual meeting of the american association for cancer research; 2013 apr 6-10; washington, dc. philadelphia (pa): aacr; cancer res 2013;73(8 suppl):abstract nr 2092. doi:10.1158/1538-7445.am2013-2092

Upstream product

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• 38041-19-9 4-aminotetrahydropyran 
• 156545-07-2 3,5-difluorophenylboronic acid 
• 891864-98-5 C₈H₈BrN₃ 
• 1034976-52-7 4-(4-methylpiperazin-1-yl)-2-[(tetrahydropyran-4-yl)-(2,2,2-trifluoroacetyl)amino]benzoyl chloride 
• 1034975-53-5 tert-butyl 4-(4-methylpiperazine-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoate 
• 1034975-40-0 tert-butyl 4-(4-methylpiperazin-1-yl)-2-(tetrahydropyran-4-ylamino)benzoate 
• 1034975-35-3 tert‐butyl 2‐amino‐4‐(4‐methylpiperazin‐1‐yl)benzoate 
• 942271-61-6 tert-butyl 4-(4-methylpiperazin-1-yl)-2-nitrobenzoate 
• 942271-60-5 tert-butyl 4-fluoro-2-nitrobenzoate 
• 394-01-4 4-fluoro-2-nitrobenzoic acid 
• 1108745-30-7 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine 
• 1108745-25-0 5-(3,5-difluorobenzyl)-2-fluorobenzonitrile 
• 141776-91-2 1-bromomethyl-3,5-difluoro-benzene 

Downstream Products

• 1108744-37-1 ethyl 5-(3,5-difluorobenzyl)-3-({[4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl]carbonyl}amino)-1H-indazole-1-carboxylate 

Relevant articles and documents

Preparation method of entrectinib

The invention provides a preparation method of entrectinib. According to the invention, the route reaction steps are few, and the total yield of the reaction is increased; and the route is mature, the reaction condition is mild, extremely low temperature reaction is not needed, the post-treatment is simple and convenient, the synthesis of a large amount of target products is facilitated, the purity can reach 99.5% or above, and the industrial production of the product is facilitated.

Method for preparing entrectinib

The invention provides a method for preparing entrectinib. According to the method disclosed by the invention, the number of reaction steps is small, and the total yield of the reaction is improved; and the route is mature, the reaction condition is mild, extremely low temperature reaction is not needed, the post-treatment is simple and convenient, the synthesis of a large amount of target products is facilitated, the purity can reach 99.8%, and the industrial production of the product is facilitated.

Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.